Dilated Cardiomyopathy (DCM) accounts for the majority of cases of non-ischemic heart failure. The molecular mechanisms at the origin of this disease remain unknown therefore such cases are labeled as idiopathic (iDCM). Progressive misfolding of proteins is a common cause of many apparently unrelated chronic diseases such as primary systemic amyloidosis, diabetes, cystic fibrosis, neurodegenerative diseases and inclusion body myositis. Although the molecular mechanisms by which these pathologies develop might be different, they are recently been proposed to be all viewed as conformational diseases where the hallmark is the accumulation of intracellular or extracellular protein aggregates. Here we propose that protein misfolding can be at the basis of at least some cases of iDCM and we propose to investigate the mechanism for PSEN sequence variants in directly mediating contractile dysfunction. This hypothesis is based upon the observation that, in the majority of samples of iDCM patients, cytosolic aggregates are present in greater quantities than seen in age matched donor hearts suggesting the common pathogenetic background with other diseases of protein misfolding. However, the causal relationship between protein misfolding and disease development remains inconclusive also for the known diseases of protein misfolding such as Alzheimer Disease. Similarly to cases of early onset familial Alzheimer Disease, mutations in the PSEN1 and 2 genes have been described to segregate with familial DCM cases. We also showed that genetic variations in PSEN linked to AD occur in our population of sporadic cases of iDCM and in these cases, we described two new genetic variants in the promoter region of PSEN. These variants we described lead to reduced transcriptional activity of the gene and reduced expression of presenilin protein indicative of a loss of function of the encoded protein Presenilin. Since Presenilin has been shown to bind Ca2+ cycling proteins such as SERCA (2b and 2a) and the loss of function of PSEN in vitro lead to reduced SERCA2b activity, this observation raised the possibility that the known abnormalities in Ca2+ homeostasis described in the failing heart originate at least in part by abnormal presenilin function. PSEN may therefore play an important role in the heart and, when mutated, can contribute to cardiac dysfunction by directly affecting Ca2+ handling protein function and consequently Ca2+ dynamics. To test this hypothesis we will take advantage of mice models of Alzheimer Disease carrying mutations in PSEN1 or with gene KO. We will also apply the in-house technology of gene transfer to determine the function of the genetic fingerprint associated with iDCM in humans. Dissecting the mechanism for presenilin effect on cardiac function is instrumental for a better understanding of the origin of at least a subset of cases of iDCM. The incidence, prognosis and therapeutic option for iDCM therefore may be greatly advanced by establishing a fundamental understanding of key factors leading to the disease. PUBLIC HEALTH RELEVANCE: The majority of cases of Congestive Heart Failure (HF) are ischemic in origin. The second most frequent origin of non-ischemic HF is idiopathic dilated cardiomyopathy (DCM) of unknown cause. Recent studies highlight the recognition of the public health importance of a large number of diseases associated with defective folding of proteins leading to the accumulation of cytotoxic protein aggregates named conformational diseases. Preliminary evidence suggests that iDCM may be included among these misfolding diseases and dissecting the mechanisms is instrumental for potential interventions targeted to the cause of the dysfunction.